1. Field of the Invention
This invention relates to the use of EGF receptor inhibitors, especially those occuring naturally in produce, foodstuffs, and the like, such as the isoflavinoid genistein, for preventing unwanted side effects when retinoids are used topically for treating humans.
2. The State of the Art
Topical retinoid administration has been used to treat a wide variety of dermatological ailments. For example, acne vulgaris has been treated with all-trans retinoic acid (tretinoin), sold under the well-known brand name Retin-A (from Janssen Pharmaceuticals), and the lesser known brand name Avita (from Penederm); oral 13-cis retinoic acid (isotretinoin; sold under the brand name Accutane for oral administration) has been used for severe cases of acne. 9-cis retinoic acid (alitretinoin) has been used topically to treat cutaneous lesions of AIDS-related Kaposi""s sarcoma (Panretin brand gel, from Ligand Pharmaceuticals), and systemically to treat chronic eczema and renal cancer. Synthetic retinoids that have been approved for use against acne and psoriasis include adapalene (sold under the brand Differin) and tazarotene (sold under the brand name Tazorac), respectively. Psoriasis also has been treated with the trimethylmethoxyphenyl analogue of retinoic acid ethyl ester (etretinate; sold under the brand names Soriatane (acetretin), and formerly Tegison (etretinate)). Retinoids have also been used for treating other kinds of acne (such as cystic acne and acne rosacea) and various keratinization disorders (such as, ichthyoses (such as lamellar ichthyosis, ichthyosis vulgaris), pityriasis rubra pilaris, and Darier""s disease). Retinoids have also been used for skin cancer and chemotheraphy of precancerous lesions and chemoprophylaxis (such as for basal cell and squamous cell carcinomas and keratoacanthoma). Retinoids have also been used for treating such skin conditions as warts, hyperkaratotic eczema of the hands and feet, and cutaneous sarcoidosis. In addition, retinoids have been used for treating photoaged skin, with compositions such as sold under the brand name Renova. Thus, retinoids are widely used both topically and systemically (orally) for a wide variety of conditions.
The present inventors and those working with them have invented other uses for retinoids, including preventing photoaging of human skin (e.g., U.S. Pat. Nos. 5,837,224, 6,130,254, and application No. 615218, filed Jul. 13, 2000), preventing and reversing chronological aging of human skin (e.g., application No. 28,435, filed Feb. 24, 1998), treating post-inflammatory hyperpigmentation in black skin (e.g., U.S. Pat. Nos. 5,750,570 and 6,017,960), preventing UV-induced loss of collagen biosynthesis (e.g., application No. 285,860, filed Apr. 2, 1999), prevention of UV-induced functional vitamin A deficiency (e.g., application No. 418,413, filed Oct. 14 1999), preventing scarring and inflammation due to acne (e.g., 576,597, filed May 22, 2000). The disclosures of these patents and applications are incorporated herein by reference.
While those trained in the use of retinoids are cognizant of toxicity issues, much more common and predictable are common side effects, such as erythema (redness), scaling, burning, and/or pruritus (itching), especially when retinoids are used long term. E.g., J W Fluhr et al., xe2x80x9cTolerance profile of retinol, retinaldehyde and retinoic acid under maximized and long-term clinical conditionsxe2x80x9d, Dermatology 1999; 199 Suppl 1:57-60.
Protein tyrosine kinases are involved in regulating critical functions in mammalian cells (e.g., cell growth, cell death, inflammation, and so on). There are two classes of protein tyrosine kinases: receptor protein tyrosine kinases and non-receptor protein tyrosine kinases. Many growth factor receptors on cell surfaces have intrinsic protein tyrosine kinase activity (i.e., the receptor protein kinases), so that when the growth factor binds to its receptor on the cell surface, it stimulates the intracellular protein tyrosine kinase activity. This intrinsic activation initiates a signal transduction cascade that typically results in cell growth and survival (e.g., effects expected from growth factors).
EGFR (Epidermal Growth Factor Receptor) is a transmembrane protein that includes a bound protein tyrosine kinase (PTK) in the intracellular or cytoplasmic portion, and hence the EGFR has xe2x80x9cintrinsicxe2x80x9d protein tyrosine kinase activity. After EGF binds to the extracellular portion of the EGFR, the intracellular portion having the PTK moiety can be activated by phosphorylation with ATP (adenosine triphosphate), releasing ADP in the process. When the PTK enzyme portion of the EGFR is activated, it acts on its substrate, which is another EGFR (if one is nearby). (Depending on the particular receptor, there may be a few receptors or there may be thousands of receptors in a given cell""s membrane.) The activated EGFR activates an adjacent EGFR by phosphorylating its cytoplasmic portion (which contains the bound PTK) with the ATP. The phosphorylated EGFR (EGF-R-{circle around (P)}) with the active PTK enzyme catalyzes various reactions that result in nuclear signalling, up-regulating or down-regulating various genes, with concommitant effects on the cell. While this activation is occurring, the first EGFR bound to the EGF may then bind to another ATP and activate the cytoplasmic portion of yet another EGFR, increasing the nuclear signalling. Thus, as EGFRs are activated, they can activate other EGFRs so that the entire signal is amplified.
In one mode of action, it is known that retinoids cause an elevation in the heparin-binding epidermal growth factor (HB-EGF; one member of the EGF family that binds the EGFR), which, through the nuclear signalling just discussed, causes hyperplasia and subsequent scaling and peeling of the skin, a side effect common to many who use retinoids topically. (E.g., J-H Xiao et al., xe2x80x9cIdentification of heparin-binding EGF-like growth factor as a target in intercellular regulation of epidermal basal cell growth by suprabasal retinoic acid receptorsxe2x80x9d, The EMBO J., Vol. 18, No. 6, pp. 1539-1548 (1999).) When a pharmacological retinoid is applied topically to skin or taken orally, the EGFR (epidermal growth factor receptor) is activated by the release of HB-EGF. The EGFRs are located on cells in the epidermis, and their activation causes the cells in the lower epidermis to proliferate excessively. The excessively proliferating cells cause upward pressure on the outward migrating cells, resulting in an excessive number of cells arriving at the surface of the skin. This hyperproliferation is manifest as peeling, scaling, and/or dryness of the skin. Retinoids have other modes of action, but this mode is believed to be responsible for many of the side effects that deter patients from continued use of retinoid therapy or decrease the benefit they receive (subjectively trading the discomfort of one problem for a lesser problem). Other than terminating therapy, topically applied emollients, moisturizers, humectants, and the like are the typical adjuncts to topical retinoid therapy for mitigating these detrimental side effects. In human skin organ culture it was shown that synthetic EGFR tyrosine kinase inhibitors blocked actions of HB-EGF induced by micromolar concentrations of retinoic acid. (S. W. Stoll and J. T. Elder, xe2x80x9cRetinoid regulation of heparin-binding EGF-like growth factor gene expression in human keratinocytes and skinxe2x80x9d, Exp. Dermatol., 1998: 7:391-397.) More particularly, it was shown that after exposure to a retinoid, the HB-EGF increased, but the EGFR tyrosine kinase inhibitors prevented this increase from causing hyperplasia.
The medical arts have been focussing on the EGFR in connection with anti-cancer therapies because links have been shown between the EGFR subfamily of tyrosine kinases and human cancers, including that various tumors express EGFR. Thus, researchers have been looking towards tyrosine kinase inhibitors as anticancer agents because of the existence of EGFR expression by tumor cells. F. Ciardiello, xe2x80x9cEpidermal Growth Factor Receptor Tyrosine Kinase Inhibitors as Anticancer Agentsxe2x80x9d, Drugs 2000, 60 Suppl. 1, 25-32; and E. Raymond et al., xe2x80x9cEpidermal Growth Factor Receptor Tyrosine Kinase as a Target for Anticancer Therapyxe2x80x9d, id. at 15-23 (the disclosures of which are incorporated herein by reference). These inhibitory compounds include an extremely wide variety of molecules, including monoclonal antibodies, immunotoxin conjugates, ligand-toxin recombinant proteins, EGFR protein tyrosine kinase inhibitors, and tyrosine kinase inhibitor-ligand conjugates. As the identified cancers that express EGFR include lung, colorectal, advanced gastric, pancreatic, ovarian, breast, and prostate, administration of these compounds is by injection (system or direct acting) or orally. Additionally, more advanced synthetic compounds are more selective and more potent than more naturally occuring compounds. The nuclear signalling mediated by EGFRs can be decreased by inhibiting the binding of EGF to the receptor, by inhibiting the binding of the EGF-EGFR complex to ATP, and/or by inhibiting the activation of the EGFR substrate by (EGF-R-{circle around (P)}).
Certain inhibitors of protein tyrosine kinase at lower concentrations inhibit other tyrosine kinases at higher concentrations. Among these are EGF-R inhibitors including AG-494 (a member of the tyrphostin family of tyrosine kinase inhibitors), AG-825 (5-[(Benzthiazol-2-yl)thiomethyl]-4-hydroxy-3-methoxybenzylidenecyanoacetamide), AG-1478 (4-(3-Chloroanilino)-6,7-dimethoxyquinazoline) and 4-aniloquinazoline derivatives (W. A. Denny, xe2x80x9cThe 4-anilinoquinazoline class of inhibitors of the erbB family of receptor tyrosine kinases,xe2x80x9d Farmaco 2001 January-February;56(1-2):51-6, discussing both reversibly and irreversibly binding analogs), EI-146 (an Erbstatin analog), methyl-2,5-dihydroxycinnamate, HDBA (2-Hydroxy-5-(2,5-dihydroxybenzylamino)-2-hydroxybenzoic acid; Onoda et al., J. Natural Products, 52:1252, 1989), Lavendustin A, RG-13022 (a non-phenolic tyrphostin analog which inhibits the EGFR), RG-14620 (a non-phenolic tyrphostin analog which is selective for the EGFR and long acting), Tyrphostin 23 (RG-50810), Tyrphostin 25 ([(3,4,5-trihydroxyphenyl)-methylene]-propanedinitrile, Gazit et al., J. Med. Chem., 32:2344, 1989; also known as RG-50875), Tyrphostin 46, Tyrphostin 47 (also known as RG-50864 and AG-213), Tyrphostin 51, and Tyrphostin 1.
A review article by S. B. Noonberg and C. C. Benz (xe2x80x9cTyrosine Kinase inhibitors Targeted to the Epidermal Growth Factor Receptor Subfamilyxe2x80x94Role as Anticancer Agentsxe2x80x9d, Drugs, 2000 Apr:59(4) (the disclosure of which is incorporated herein by reference)) describes various approaches for inhibiting the kinase activity of EGF receptors, including antibodies, immunotoxin conjugates, ligand-binding cytotoxic agents, and small molecule kinase inhibitors.
Small nucleotide inhibitors have also been developed for inhibiting EGFR, as well as for such kinases as JNK, MEKK, and others that activate EGFR signalling. Exemplary U.S. Pat. Nos. include 5,914,269 and 6,187,585 for EGFR inhibition, 5,877,309, 6,133,246, and 6,221,850 for JNK inhibition, 6,168,950 for MEKK inhibition, and other such as 6,054,440, 6,159,697, and 6,262,241 (the disicosures of which are all incorporated herein by reference). Most are disclosed as suitable for transdermal administration to affect the local dermis, via reference to textbook methods for preparing topically-applied compositions, although no reason is given for such treatment (i.e., no dermal condition is identified that might be treated by such therapy), nor is any efficacy shown for transdermal delivery (i.e., there is no evidence that small nucleotide inhibitors can be applied
In light of the foregoing, it would be beneficial to prevent the peeling, scaling, and dryness that accompanies topical and systemic (oral) retinoid therapy without significantly diminishing the desired therapeutic effect, whether by antagonism, competition, or otherwise. It would also be useful to provide this benefit without interfering with or complicating the retinoid treatment regimen, thereby maintaining if not improving patient compliance with the retinoid therapy.
Towards this end, we have discovered that adminstration of one or more compounds that inhibit EGFR signalling reduces the peeling, scaling, and dryness side effects of therapeutically-administered retinoids. Preferably, these compounds include naturally occuring products, such as isoflavones, one example of which is genistein (which is found in raw soy products), although synthetic analogs thereof are also likely to be useful. The inhibitor may a reversible inhibitor, it may irreversibly bind the receptor, or a combination thereof may be used. Preferably, the admistration of the EGFR inhibitor is topically.
Accordingly, this invention provides a method for diminishing the side effects of topical and systemic retinoid therapy through the use of application of an EGFR inhibitor, preferably a natural product, and preferably by topical administration. The administration can be concurrent with the retinoid therapy, such as administering a composition comprising both a retinoid and a natural EGFR inhibitor, it can be administered as desired by the patient, such as with a separate composition comprising a natural EGFR inhibitor and applied as needed by the patient, or it can be a combination of these methods.
In addition, in another embodiment this invention alleviates the symptom of peeling due to hyperproliferation, regardless of the source of the proliferation (which can range from retinoid therapy to sunburn).
In other embodiments, this invention provides various compositions suitable for topical and systemic application to human skin, including a composition comprising a retinoid and an EGFR inhibitor, preferably a composition comprising a combination of a retinoid and a natural EGFR inhibitor, as well as a topical composition comprising an EGFR inhibitor and an emollient, moisturizer, and/or humectant.
In yet another embodiment, this invention provides a cleanser composition, and a composition for ameliorating irritation due to soaps and other compositions causing contact dermatitis characterized by hyperproliferation. More specifically, in one aspect this invention provides a cleanser, comprising a soap or surfactant and an EGFR inhibitor, more preferably an isoflavinoid such as genistein, or a ground or powdered botanical, such as soybeans which contain genistein. In another aspect, the invention provides a dispersion and/or suspension of an EGFR inhibitor, more preferably an isoflavinoid such as genistein, or a ground or powdered botanical, such as soybeans which contain genistein, in a form such as a lotion or cream, for treating contact dermatitis characterized by hyperproliferation.